The effect of nirmatrelvir‐ritonavir on viral clearance and length of hospital stay in patients infected with SARS‐CoV‐2 omicron variants

Abstract Background The pandemic of coronavirus disease 2019 (COVID‐19) has caused heavy burdens on national healthcare systems. Nirmatrelvir‐ritonavir (Paxlovid) may be one of the most promising therapeutic drugs, with reports of up to 89% reduction rates in hospitalization risk and death among patients with mild‐to‐moderate COVID‐19 who are at risk of developing severe disease. However, limited studies have investigated the effects of this class of drugs on viral clearance and length of hospital stay. Methods In this study, we retrospectively analyzed the characteristics of patients infected with the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and investigated the effects of oral nirmatrelvir‐ritonavir on viral clearance and length of hospital stay in mild‐to‐moderate COVID‐19 patients at high risk for progression to severe disease. Results The median SARS‐CoV‐2 negative conversion time was 16 (13–20) versus 13 (10–16) days (control group versus nirmatrelvir‐ritonavir group, p < 0.001), the median length of hospital stay was 13 (10–16) versus 12 (13–14) days (control group versus nirmatrelvir‐ritonavir group, p = 0.01), and the SARS‐CoV‐2 negative conversion time and length of hospital stay were significantly shorter in the nirmatrelvir‐ritonavir group than in the control group. When controlling for hypertension, chronic kidney disease, severity status of COVID‐19, use of antibiotic agent, and COVID‐19 vaccine received, multiple stepwise linear regression analysis showed that nirmatrelvir‐ritonavir treatment was negatively associated with the SARS‐CoV‐2 negative conversion time and length of hospital stay. Conclusion Nirmatrelvir‐ritonavir reduces the viral clearance time and length of hospital stay in hospitalized patients with COVID‐19. Nirmatrelvir‐ritonavir might be a promising drug to reduce the virus load and the heavy burden of healthcare systems.


| INTRODUCTION
The pandemic of coronavirus disease 2019 (COVID-19) has caused heavy burdens on national healthcare systems. With increasing morbidity and death counts, the need for novel and effective oral antiviral drugs for the control of COVID-19 is unmet. Nirmatrelvir-ritonavir (Paxlovid) may be one of the most promising therapeutic drugs, with reports of up to 89% reduction rates in hospitalization risk and death among patients with mild-to-moderate COVID-19 who are at risk of developing severe disease. 1 As a combination protease inhibitor, nirmatrelvir-ritonavir targets the major protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to block viral replication. 2

| METHOD
In this retrospective observational study, we investigated the effects of oral nirmatrelvir-ritonavir on viral clearance and length of hospital stay in mild-to-moderate COVID-19 patients at high risk for progression to severe disease. All data were obtained from the medical records of patients infected with the SARS-CoV-2 Omicron variant between April 12, 2022 and June 15, 2022 in Shidong hospital. In total, 760 patients were included. SARS-CoV-2 infection was diagnosed via real-time polymerase chain reaction (RT-PCR) from nasopharyngeal swabs. Patients who have at least one characteristic or condition associated with high risk of progression to severe Covid-19 were included. 1

| RESULTS
The characteristics of patients were shown in Table 1 Table 2). This also showed that hospitalized patients with COVID-19 who received nirmatrelvir-ritonavir had significantly more rapid viral clearance and shorter length of hospital stay than those who did not receive nirmatrelvir-ritonavir.

| DISCUSSION
Nirmatrelvir-ritonavir is an important treatment that can be added to therapeutic regimens for early treatment of COVID-19 to reduce incidence of severe disease, hospitalization, and/or death. 4,5 A previous study in healthy adults showed that nirmatrelvir was well tolerated, safe, and effective in increasing plasma concentrations. 6  showed faster decreased viral loads than those not treated with nirmatrelvir-ritonavir. 9 Our study showed that nirmatrelvir-ritonavir was associated with decreased SARS-CoV-2 negative conversion time. Moreover, we found that nirmatrelvir-ritonavir use could also reduce the length of hospital stay. These results support the use of nirmatrelvir-ritonavir for hospitalized COVID-19 patients with SARS-CoV-2 Omicron variant. Due to that viral shedding persists for a longer period will prolong deisolation and hospital stay thus increase the financial burden, nirmatrelvir-ritonavir might be a promising drug to reduce the virus load and the heavy burden of healthcare systems.
Previous studies suggested that SARS-CoV-2 Omicron variant caused very high risk of infection but less severe cases or death 10,11 ; in this study, there were no hospitalized patients who died or experienced severe COVID-19, so we did not analyze the effect of nirmatrelvir-ritonavir treatment on reducing the progression of severe COVID-19 and mortality. Case reports have documented that some patients who have completed one course (5 days) of nirmatrelvirritonavir experienced rebound of COVID-19 infections [12][13][14] ; recently, we also reported a rapid COVID-19 rebound in a severe COVID-19 patient during a 20-day course of nirmatrelvir-ritonavir. 15 This study was unable to analyze the association between nirmatrelvir-ritonavir use and recurrence of COVID-19 symptoms because a follow-up retrospective study was lacking. Moreover, another limitation was that data on viral load were lacking in our study; therefore, the effect of nirmatrelvir-ritonavir use on viral load could not be analyzed.

PEER REVIEW
The peer review history for this article is available at https://publons. com/publon/10.1111/irv.13095.

DATA AVAILABILITY STATEMENT
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.